Autism Gene Ube3a and Seizures Impair Sociability by Repressing VTA Cbln1

Overview

Journal Nature

Specialty Science

Date 2017 Mar 16

PMID 28297715

Citations 80

Authors

Vaishnav Krishnan

David C Stoppel

Yi Nong

Mark A Johnson

Monica J S Nadler

Ekim Ozkaynak

Brian L Teng

Ikue Nagakura

Fahim Mohammad

Michael A Silva

Sally Peterson

Tristan J Cruz

Ekkehard M Kasper

Ramy Arnaout

Matthew P Anderson

Affiliations

Soon will be listed here.

Abstract

Maternally inherited 15q11-13 chromosomal triplications cause a frequent and highly penetrant type of autism linked to increased gene dosages of UBE3A, which encodes a ubiquitin ligase with transcriptional co-regulatory functions. Here, using in vivo mouse genetics, we show that increasing UBE3A in the nucleus downregulates the glutamatergic synapse organizer Cbln1, which is needed for sociability in mice. Epileptic seizures also repress Cbln1 and are found to expose sociability impairments in mice with asymptomatic increases in UBE3A. This Ube3a-seizure synergy maps to glutamate neurons of the midbrain ventral tegmental area (VTA), where Cbln1 deletions impair sociability and weaken glutamatergic transmission. We provide preclinical evidence that viral-vector-based chemogenetic activation of, or restoration of Cbln1 in, VTA glutamatergic neurons reverses the sociability deficits induced by Ube3a and/or seizures. Our results suggest that gene and seizure interactions in VTA glutamatergic neurons impair sociability by downregulating Cbln1, a key node in the expanding protein interaction network of autism genes.

Citing Articles

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